The SV2A ligand levetiracetam inhibits presynaptic Ca2+ channels via an intracellular pathway

Levetiracetam (LEV) is a prominent antiepileptic drug (AED) which binds to neuronal synaptic vesicle glycoprotein 2A (SV2A) protein and has reported effects on ion channels, but retains a poorly-defined mechanism of action. Here, we investigate inhibition of voltage-dependent Ca2+ (CaV) channels as a potential mechanism by which LEV imparts effects on neuronal activity. We used electrophysiological methods to investigate the effects of LEV on cholinergic synaptic transmission and CaV channel activity in superior cervical ganglion neurons (SCGNs). In parallel, we investigated effects of the LEV ‘inactive’ R-enantiomer, UCB L060. Thus, LEV, but not UCB L060 (each 100 μM), inhibited synaptic transmission between SCGNs in long-term culture in a time-dependent manner, significantly reducing excitatory postsynaptic potentials (EPSP) following ≥30 min application. In isolated SCGNs, LEV pretreatment (≥1 h), but not acute (5 min) application, significantly inhibited whole-cell IBa amplitude. In current clamp recordings, LEV reduced the amplitude of the afterhyperpolarizing potential (AHP) in a Ca2+-dependent manner, but also increased action potential (AP) latency in a Ca2+-independent manner, suggesting further mechanisms associated with reduced excitability. Intracellular LEV application (4-5 min) caused a rapid inhibition of IBa amplitude to an extent comparable to that seen following extracellular LEV pretreatment ( ≥ 1 h). Neither pretreatment nor intracellular application of UCB L060 produced any inhibitory effects on IBa amplitude. These results identify a stereospecific intracellular pathway by which LEV inhibits presynaptic CaV channels; resultant reductions in neuronal excitability are proposed to contribute to the anticonvulsant effects of LEV.

Preventing carbon contamination of optical devices for X-rays: the effect of oxygen on photon-induced dissociation of CO on platinum

Platinum is one of the most common coatings used to optimize mirror reflectivity in soft X-ray beamlines. Normal operation results in optics contamination by carbon-based molecules present in the residual vacuum of the beamlines. The reflectivity reduction induced by a carbon layer at the mirror surface is a major problem in synchrotron radiation sources. A time-dependent photoelectron spectroscopy study of the chemical reactions which take place at the Pt(111) surface under operating conditions is presented. It is shown that the carbon contamination layer growth can be stopped and reversed by low partial pressures of oxygen for optics operated in intense photon beams at liquidnitrogen temperature. For mirrors operated at room temperature the carbon contamination observed for equivalent partial pressures of CO is reduced and the effects of oxygen are observed on a long time scale.

A time-domain probe method for three-dimensional rough surface reconstructions

The task of this paper is to develop a Time-Domain Probe Method for the reconstruction of impenetrable scatterers. The basic idea of the method is to use pulses in the time domain and the time-dependent response of the scatterer to reconstruct its location and shape. The method is based on the basic causality principle of timedependent scattering. The method is independent of the boundary condition and is applicable for limited aperture scattering data. In particular, we discuss the reconstruction of the shape of a rough surface in three dimensions from time-domain measurements of the scattered field. In practise, measurement data is collected where the incident field is given by a pulse. We formulate the time-domain fieeld reconstruction problem equivalently via frequency-domain integral equations or via a retarded boundary integral equation based on results of Bamberger, Ha-Duong, Lubich. In contrast to pure frequency domain methods here we use a time-domain characterization of the unknown shape for its reconstruction. Our paper will describe the Time-Domain Probe Method and relate it to previous frequency-domain approaches on sampling and probe methods by Colton, Kirsch, Ikehata, Potthast, Luke, Sylvester et al. The approach significantly extends recent work of Chandler-Wilde and Lines (2005) and Luke and Potthast (2006) on the timedomain point source method. We provide a complete convergence analysis for the method for the rough surface scattering case and provide numerical simulations and examples.

Phosphorylation of the voltage-gated potassium channel Kv2.1 by AMP-activated protein kinase regulates membrane excitability

Firing of action potentials in excitable cells accelerates ATP turnover. The voltage-gated potassium channel Kv2.1 regulates action potential frequency in central neurons, whereas the ubiquitous cellular energy sensor AMP-activated protein kinase (AMPK) is activated by ATP depletion and protects cells by switching off energy-consuming processes. We show that treatment of HEK293 cells expressing Kv2.1 with the AMPK activator A-769662 caused hyperpolarizing shifts in the current-voltage relationship for channel activation and inactivation. We identified two sites (S440 and S537) directly phosphorylated on Kv2.1 by AMPK and, using phosphospecific antibodies and quantitative mass spectrometry, show that phosphorylation of both sites increased in A-769662-treated cells. Effects of A-769662 were abolished in cells expressing Kv2.1 with S440A but not with S537A substitutions, suggesting that phosphorylation of S440 was responsible for these effects. Identical shifts in voltage gating were observed after introducing into cells, via the patch pipette, recombinant AMPK rendered active but phosphatase-resistant by thiophosphorylation. Ionomycin caused changes in Kv2.1 gating very similar to those caused by A-769662 but acted via a different mechanism involving Kv2.1 dephosphorylation. In cultured rat hippocampal neurons, A-769662 caused hyperpolarizing shifts in voltage gating similar to those in HEK293 cells, effects that were abolished by intracellular dialysis with Kv2.1 antibodies. When active thiophosphorylated AMPK was introduced into cultured neurons via the patch pipette, a progressive, time-dependent decrease in the frequency of evoked action potentials was observed. Our results suggest that activation of AMPK in neurons during conditions of metabolic stress exerts a protective role by reducing neuronal excitability and thus conserving energy.

Transient climate change simulations with a coupled atmosphere–ocean GCM including the tropospheric sulfur cycle

The time-dependent climate response to changing concentrations of greenhouse gases and sulfate aerosols is studied using a coupled general circulation model of the atmosphere and the ocean (ECHAM4/OPYC3). The concentrations of the well-mixed greenhouse gases like CO2, CH4, N2O, and CFCs are prescribed for the past (1860–1990) and projected into the future according to International Panel on Climate Change (IPCC) scenario IS92a. In addition, the space–time distribution of tropospheric ozone is prescribed, and the tropospheric sulfur cycle is calculated within the coupled model using sulfur emissions of the past and projected into the future (IS92a). The radiative impact of the aerosols is considered via both the direct and the indirect (i.e., through cloud albedo) effect. It is shown that the simulated trend in sulfate deposition since the end of the last century is broadly consistent with ice core measurements, and the calculated radiative forcings from preindustrial to present time are within the uncertainty range estimated by IPCC. Three climate perturbation experiments are performed, applying different forcing mechanisms, and the results are compared with those obtained from a 300-yr unforced control experiment. As in previous experiments, the climate response is similar, but weaker, if aerosol effects are included in addition to greenhouse gases. One notable difference to previous experiments is that the strength of the Indian summer monsoon is not fundamentally affected by the inclusion of aerosol effects. Although the monsoon is damped compared to a greenhouse gas only experiment, it is still more vigorous than in the control experiment. This different behavior, compared to previous studies, is the result of the different land–sea distribution of aerosol forcing. Somewhat unexpected, the intensity of the global hydrological cycle becomes weaker in a warmer climate if both direct and indirect aerosol effects are included in addition to the greenhouse gases. This can be related to anomalous net radiative cooling of the earth’s surface through aerosols, which is balanced by reduced turbulent transfer of both sensible and latent heat from the surface to the atmosphere.

The stability of a two-dimensional vorticity filament under uniform strain

The quantitative effects of uniform strain and background rotation on the stability of a strip of constant vorticity (a simple shear layer) are examined. The thickness of the strip decreases in time under the strain, so it is necessary to formulate the linear stability analysis for a time-dependent basic flow. The results show that even a strain rate γ (scaled with the vorticity of the strip) as small as 0.25 suppresses the conventional Rayleigh shear instability mechanism, in the sense that the r.m.s. wave steepness cannot amplify by more than a certain factor, and must eventually decay. For γ < 0.25 the amplification factor increases as γ decreases; however, it is only 3 when γ e 0.065. Numerical simulations confirm the predictions of linear theory at small steepness and predict a threshold value necessary for the formation of coherent vortices. The results help to explain the impression from numerous simulations of two-dimensional turbulence reported in the literature that filaments of vorticity infrequently roll up into vortices. The stabilization effect may be expected to extend to two- and three-dimensional quasi-geostrophic flows.

On the 'downward control' of extratropical diabatic circulations by eddy-induced mean zonal forces

The situation considered is that of a zonally symmetric model of the middle atmosphere subject to a given quasi-steady zonal force F̄, conceived to be the result of irreversible angular momentum transfer due to the upward propagation and breaking of Rossby and gravity waves together with any other dissipative eddy effects that may be relevant. The model's diabatic heating is assumed to have the qualitative character of a relaxation toward some radiatively determined temperature field. To the extent that the force F̄ may be regarded as given, and the extratropical angular momentum distribution is realistic, the extratropical diabatic mass flow across a given isentropic surface may be regarded as controlled exclusively by the F̄ distribution above that surface (implying control by the eddy dissipation above that surface and not, for instance, by the frequency of tropopause folding below). This “downward control” principle expresses a critical part of the dynamical chain of cause and effect governing the average rate at which photochemical products like ozone become available for folding into, or otherwise descending into, the extratropical troposphere. The dynamical facts expressed by the principle are also relevant, for instance, to understanding the seasonal-mean rate of upwelling of water vapor to the summer mesopause, and the interhemispheric differences in stratospheric tracer transport. The robustness of the principle is examined when F̄ is time-dependent. For a global-scale, zonally symmetric diabatic circulation with a Brewer-Dobson-like horizontal structure given by the second zonally symmetric Hough mode, with Rossby height HR = 13 km in an isothermal atmosphere with density scale height H = 7 km, the vertical partitioning of the unsteady part of the mass circulation caused by fluctuations in F̄ confined to a shallow layer LF̄ is always at least 84% downward. It is 90% downward when the force fluctuates sinusoidally on twice the radiative relaxation timescale and 95% if five times slower. The time-dependent adjustment when F̄ is changed suddenly is elucidated, extending the work of Dickinson (1968), when the atmosphere is unbounded above and below. Above the forcing, the adjustment is characterized by decay of the meridional mass circulation cell at a rate proportional to the radiative relaxation rate τr−1 divided by {1 + (4H2/HR2)}. This decay is related to the boundedness of the angular momentum that can be taken up by the finite mass of air above LF̄ without causing an ever-increasing departure from thermal wind balance. Below the forcing, the meridional mass circulation cell penetrates downward at a speed τr−1 HR2/H. For the second Hough mode, the time for downward penetration through one density scale height is about 6 days if the radiative relaxation time is 20 days, the latter being representative of the lower stratosphere. At any given altitude, a steady state is approached. The effect of a rigid lower boundary on the time-dependent adjustment is also considered. If a frictional planetary boundary layer is present then a steady state is ultimately approached everywhere, with the mass circulation extending downward from LF̄ and closing via the boundary layer. Satellite observations of temperature and ozone are used in conjunction with a radiative transfer scheme to estimate the altitudes from which the lower stratospheric diabatic vertical velocity is controlled by the effective F̄ in the real atmosphere. The data appear to indicate that about 80% of the effective control is usually exerted from below 40 km but with significant exceptions up to 70 km (in the high latitude southern hemispheric winter). The implications for numerical modelling of chemical transport are noted.

Modelling the time-evolution of phytoplankton size spectra from satellite remote sensing

A dynamic size-structured model is developed for phytoplankton and nutrients in the oceanic mixed layer and applied to extract phytoplankton biomass at discrete size fractions from remotely sensed, ocean-colour data. General relationships between cell size and biophysical processes (such as sinking, grazing, and primary production) of phytoplankton were included in the model through a bottom–up approach. Time-dependent, mixed-layer depth was used as a forcing variable, and a sequential data-assimilation scheme was implemented to derive model trajectories. From a given time-series, the method produces estimates of size-structured biomass at every observation, so estimates seasonal succession of individual phytoplankton size, derived here from remote sensing for the first time. From these estimates, normalized phytoplankton biomass size spectra over a period of 9 years were calculated for one location in the North Atlantic. Further analysis demonstrated that strong relationships exist between the seasonal trends of the estimated size spectra and the mixed-layer depth, nutrient biomass, and total chlorophyll. The results contain useful information on the time-dependent biomass flux in the pelagic ecosystem.

Money enhances memory consolidation – but only for boring material

Money’s ability to enhance memory has received increased attention in recent research. However, previous studies have not directly addressed the time-dependent nature of monetary effects on memory, which are suggested to exist by research in cognitive neuroscience, and the possible detrimental effects of monetary rewards on learning interesting material, as indicated by studies in motivational psychology. By utilizing a trivia question paradigm, the current study incorporated these perspectives and examined the effect of monetary rewards on immediate and delayed memory performance for answers to uninteresting and interesting questions. Results showed that monetary rewards promote memory performance only after a delay. In addition, the memory enhancement effect of monetary rewards was only observed for uninteresting questions. These results are consistent with both the hippocampus-dependent memory consolidation model of reward learning and previous findings documenting the ineffectiveness of monetary rewards on tasks that have intrinsic value.

Solvent-Dependent Formation of Os(0) Complexes by Electrochemical Reduction of [Os(CO)(2,2′-bipyridine)(L)Cl2]; L = Cl−,PrCN

Cyclic voltammetry and ultraviolet−visible/infrared (UV−vis/IR) spectroelectrochemistry were used to study the cathodic electrochemical behavior of the osmium complexes mer-[OsIII(CO) (bpy)Cl3] (bpy = 2,2′-bipyridine) and trans(Cl)-[OsII(CO) (PrCN)(bpy)Cl2] at variable temperature in different solvents (tetrahydrofuran (THF), butyronitrile (PrCN), acetonitrile (MeCN)) and electrolytes (Bu4NPF6, Bu4NCl). The precursors can be reduced to mer-[OsII(CO) (bpy•−)Cl3]2− and trans(Cl)-[OsII(CO)(PrCN) (bpy•−)Cl2]−, respectively, which react rapidly at room temperature, losing the chloride ligands and forming Os(0) species. mer-[OsIII(CO) (bpy)Cl3] is reduced in THF to give ultimately an Os−Os-bonded polymer, probably [Os0(CO) (THF)-(bpy)]n, whereas in PrCN the well-soluble, probably mononuclear [Os0(CO) (PrCN)(bpy)], species is formed. The same products were observed for the 2 electron reduction of trans(Cl)-[OsII(CO)(PrCN) (bpy)Cl2] in both solvents. In MeCN, similar to THF, the[Os0(CO) (MeCN)(bpy)]n polymer is produced. It is noteworthy that the bpy ligand in mononuclear [Os0(CO) (PrCN)(bpy)] is reduced to the corresponding radical anion at a significantly less negative potential than it is in polymeric [Os0(CO) (THF)(bpy)]n: ΔE1/2 = 0.67 V. Major differences also exist in the IR spectra of the Os(0) species: the polymer shows a broad ν(CO) band at much smaller wavenumbers compared to the soluble Os(0) monomer that exhibits a characteristic ν(Pr-CN) band below 2200 cm−1 in addition to the intense and narrow ν(CO) absorption band. For the first time, in this work the M0-bpy(M = Ru, Os) mono- and dicarbonyl species soluble in PrCN have been formulated as a mononuclear complex. Density functional theory (DFT) and time-dependent-DFT calculations confirm the Os(0) oxidation state and suggest that [Os0(CO)(PrCN)(bpy)] is a square planar moiety. The reversible bpy-based reduction of [Os0(CO) (PrCN)(bpy)] triggers catalytic reduction of CO2 to CO and HCOO−.

Abrupt CO2 experiments as tools for predicting and understanding CMIP5 representative concentration pathway projections

A fast simple climate modelling approach is developed for predicting and helping to understand general circulation model (GCM) simulations. We show that the simple model reproduces the GCM results accurately, for global mean surface air temperature change and global-mean heat uptake projections from 9 GCMs in the fifth coupled model inter-comparison project (CMIP5). This implies that understanding gained from idealised CO2 step experiments is applicable to policy-relevant scenario projections. Our approach is conceptually simple. It works by using the climate response to a CO2 step change taken directly from a GCM experiment. With radiative forcing from non-CO2 constituents obtained by adapting the Forster and Taylor method, we use our method to estimate results for CMIP5 representative concentration pathway (RCP) experiments for cases not run by the GCMs. We estimate differences between pairs of RCPs rather than RCP anomalies relative to the pre-industrial state. This gives better results because it makes greater use of available GCM projections. The GCMs exhibit differences in radiative forcing, which we incorporate in the simple model. We analyse the thus-completed ensemble of RCP projections. The ensemble mean changes between 1986–2005 and 2080–2099 for global temperature (heat uptake) are, for RCP8.5: 3.8 K (2.3 × 1024 J); for RCP6.0: 2.3 K (1.6 × 1024 J); for RCP4.5: 2.0 K (1.6 × 1024 J); for RCP2.6: 1.1 K (1.3 × 1024 J). The relative spread (standard deviation/ensemble mean) for these scenarios is around 0.2 and 0.15 for temperature and heat uptake respectively. We quantify the relative effect of mitigation action, through reduced emissions, via the time-dependent ratios (change in RCPx)/(change in RCP8.5), using changes with respect to pre-industrial conditions. We find that the effects of mitigation on global-mean temperature change and heat uptake are very similar across these different GCMs.

A numerical model of the ionospheric signatures of time-varying magneticreconnection: I. ionospheric convection

This paper presents a numerical model for predicting the evolution of the pattern of ionospheric convection in response to general time-dependent magnetic reconnection at the dayside magnetopause and in the cross-tail current sheet of the geomagnetic tail. The model quantifies the concepts of ionospheric flow excitation by Cowley and Lockwood (1992), assuming a uniform spatial distribution of ionospheric conductivity. The model is demonstrated using an example in which travelling reconnection pulses commence near noon and then move across the dayside magnetopause towards both dawn and dusk. Two such pulses, 8 min apart, are used and each causes the reconnection to be active for 1 min at every MLT that they pass over. This example demonstrates how the convection response to a given change in the interplanetary magnetic field (via the reconnection rate) depends on the previous reconnection history. The causes of this effect are explained. The inherent assumptions and the potential applications of the model are discussed.

Incoherent scatter radar observations related to magnetospheric dynamics

Over the past decade incoherent scatter radars have provided fundamental observations of velocities and plasma parameters in the high-latitude ionosphere which relate to the dynamical processes responsible for the excitation of flow in the coupled solar wind-magnetosphere-ionosphere system. These observations have played a central role in inspiring a change of paradigm from a picture of quasi-steady flows parameterised by the direction of the interplanetary magnetic field to a picture of inherently time-dependent flows driven by coupling processes at the magnetopause and in the tail. Flows and particle precipitation in the dayside ionosphere are reasonably well understood in principle in terms of the effects of time-dependent reconnection at the magnetopause, though coordinated high- and low-altitude observations are lacking. Related phenomena also appear to occur in the tail, forming the “equatorward-drifting arcs” which are present during quiet times, as well as during the growth and early expansion phases of substorms. At expansion onset, the substorm bulge forms well equatorward of the arc formation region, and may take ∼ 10 min or more to reach it in its poleward expansion. Nightside ionospheric flows are then considerably perturbed by the effects of strong precipitation-induced conductivity gradients.

Flux transfer events at the dayside magnetopause: transient reconnection or magnetosheath dynamic pressure pulses?

The suggestion is discussed that characteristic particle and field signatures at the dayside magnetopause, termed “flux transfer events” (FTEs), are, in at least some cases, due to transient solar wind and/or magnetosheath dynamic pressure increases, rather than time-dependent magnetic reconnection. It is found that most individual cases of FTEs observed by a single spacecraft can, at least qualitatively, be explained by the pressure pulse model, provided a few rather unsatisfactory features of the predictions are explained in terms of measurement uncertainties. The most notable exceptions to this are some “two-regime” observations made by two satellites simultaneously, one on either side of the magnetopause. However, this configuration has not been frequently achieved for sufficient time, such observations are rare, and the relevant tests are still not conclusive. The strongest evidence that FTEs are produced by magnetic reconnection is the dependence of their occurrence on the north-south component of the interplanetary magnetic field (IMF) or of the magnetosheath field. The pressure pulse model provides an explanation for this dependence (albeit qualitative) in the case of magnetosheath FTEs, but this does not apply to magnetosphere FTEs. The only surveys of magnetosphere FTEs have not employed the simultaneous IMF, but have shown that their occurrence is strongly dependent on the north-south component of the magnetosheath field, as observed earlier/later on the same magnetopause crossing (for inbound/outbound passes, respectively). This paper employs statistics on the variability of the IMF orientation to investigate the effects of IMF changes between the times of the magnetosheath and FTE observations. It is shown that the previously published results are consistent with magnetospheric FTEs being entirely absent when the magnetosheath field is northward: all crossings with magnetosphere FTEs and a northward field can be attributed to the field changing sense while the satellite was within the magnetosphere (but close enough to the magnetopause to detect an FTE). Allowance for the IMF variability also makes the occurrence frequency of magnetosphere FTEs during southward magnetosheath fields very similar to that observed for magnetosheath FTEs. Conversely, the probability of attaining the observed occurrence frequencies for the pressure pulse model is 10−14. In addition, it is argued that some magnetosheath FTEs should, for the pressure pulse model, have been observed for northward IMF: the probability that the number is as low as actually observed is estimated to be 10−10. It is concluded that although the pressure model can be invoked to qualitatively explain a large number of individual FTE observations, the observed occurrence statistics are in gross disagreement with this model.

Low-altitude signatures of the cusp and flux transfer events

The usual interpretation of a flux transfer event (FTE) at the magnetopause, in terms of time-dependent and possibly patchy reconnection, demands that it generate an ionospheric signature. Recent ground-based observations have revealed that auroral transients in the cusp/cleft region have all the characteristics required of FTE effects. However, signatures in the major available dataset, namely that from low-altitude polar-orbiting satellites, have not yet been identified. In this paper, we consider a cusp pass of the DE-2 spacecraft during strongly southward IMF. The particle detectors show magnetosheath ion injection signatures. However, the satellite motion and convection are opposed, and we discuss how the observed falling energy dispersion of the precipitating ions can have arisen from a static, moving or growing source. The spatial scale of the source is typical of an FTE. A simple model of the ionospheric signature of an FTE reproduces the observed electric and magnetic field perturbations. Precipitating electrons of peak energy ∼100eV are found to lie on the predicted boundary of the newly-opened tube, very similar to those found on the edges of FTEs at the magnetopause. The injected ions are within this boundary and their dispersion is consistent with its growth as reconnection proceeds. The reconnection potential and the potential of the induced ionospheric motion are found to be the same (≃25kV). The scanning imager on DE-1 shows a localised transient auroral feature around DE-2 at this time, similar to the recent optical/radar observations of FTEs.